Dc. Thompson et al., EFFECT OF THE CHEMOPROTECTIVE AGENT WR-2721 ON DISPOSITION AND BIOTRANSFORMATIONS OF ORMAPLATIN IN THE FISCHER-344 RAT BEARING A FIBROSARCOMA, Cancer research, 55(13), 1995, pp. 2837-2846
The effects of the phosphorothioate agent, WR-2721, have been investig
ated with respect to the biotransformations of ormaplatin in the Fisch
er 344 rat bearing a transplanted fibrosarcoma. A number of different
paradigms of dosing route and schedule for the administration of the t
wo agents have been investigated. In the first group of experiments, W
R-2721 (200 mg/kg, i.p.) was administered 30 min before ormaplatin (12
.5 mg/kg, i.p.), and then peritoneal fluid, plasma, and tissues were h
arvested at 30 min after the ormaplatin administration. Our results su
ggest that a significant interaction between WR-2721 and ormaplatin is
occurring in the peritoneal cavity. The interaction was evident in te
rms of both effects on distribution and disposition of total platinum
and in alterations of the profiles of biotransformation products forme
d in the various tissues and fluids. Plasma protein binding of ormapla
tin was decreased by 50% in the presence of WR-2721. Total platinum in
the spleen was decreased by 66% and in the liver by 50%. There were n
o trends among the findings that would indicate any selectivity betwee
n tumor and nontumor tissue with respect to the effects of WR-2721 on
the parameters measured. Subsequent investigations examined the effect
s of dosing the WR-2721 by the i.v. route while continuing with the i.
p. administration of the ormaplatin. WR-2721 was administered either 3
0 or 5 min before the ormaplatin, and the plasma and tissues were harv
ested at 15, 30, or 60 min after ormaplatin administration. The revers
e-phase HPLC peak, which behaved chromatographically as a Pt(dach)(WR-
1065) standard, was less prominent after the i.v. administration of WR
-2721 than it was after i.p. administration under any of the paradigms
tested. There was again no evidence for selectivity between tumor and
nontumor tissue in the findings from any of the paradigms. It is conc
luded that if WR-2721 is capable of selectively protecting nontumor ti
ssue from the toxicities of platinum-based chemotherapy, it is doing s
o by some mechanism other than its selective uptake into normal tissue
and subsequent nonspecific inactivation of any reactive cytosolic pla
tinum species formed. Other possible mechanisms are briefly discussed.